Heart failure with a preserved ejection fraction (HFpEF) is an increasingly prevalent problem and particularly so amongst an aging Veterans population. It accounts for over half of all patients with heart failure. While there have been considerable advances in understanding the mechanisms and treatment of patients with heart failure when ejection fraction is reduced, there have been few advances in understanding the mechanisms or treatment of HFpEF. From a clinical standpoint, the prevalence of comorbid conditions such as obesity, diabetes, COPD and hypertension in these patients has led to the inflammatory hypothesis where HFpEF is also associated with coronary microvascular dysfunction. Nevertheless, the causal importance of inflammation and impaired coronary flow regulation in the development of the HFpEF phenotype remain unclear. Advances in understanding mechanisms of HFpEF have been limited by the lack of suitable animal models of disease. At present, the only available models involve uncontrolled chronic hypertension with severe left ventricular hypertrophy (LVH). While these have informed our understanding of hypertensive heart disease and diastolic dysfunction over the last 50 years, they may not be directly relevant to the majority of HFpEF patients. First, most patients with HFpEF have controlled or only mild systolic hypertension and LVH is frequently absent. Second, in contrast to patients with HFpEF, hypertensive heart disease progresses to systolic dysfunction (HFrEF). Thus, how the development of reduced left ventricular compliance typical of many HFpEF patients develops in the absence of sustained hypertension remains an enigma. Completed work during the previous funding period has resulted in the development of a large animal model of the HFpEF cardiac phenotype produced by repetitive brief LV pressure overload. This simulates the labile systolic hypertension typical of patients with reduced systemic arterial compliance accompanying aging where HFpEF is particularly prevalent. Initially, brief pressure overload is characterized by stretch-induced ?stunning? with focal myocyte apoptosis and troponin I release occurring in the absence of myocardial ischemia. Within 2-weeks, reduced LV compliance, myocyte loss and myocyte cellular hypertrophy develop with a prominent increase in interstitial fibrosis. This is accompanied by concentric inward LV remodeling yet, like most patients with HFpEF, the absence of severe left ventricular hypertrophy or uncontrolled hypertension at rest. The central hypothesis of this proposal is that stretch-induced myocyte injury associated with repetitive labile systolic hypertension and preload elevation leads to chronic troponin I release and a myocardial inflammatory response that is initiated by proinflammatory macrophages. This leads to myocyte loss and to the development of interstitial fibrosis. This progression can be prevented by interventions that attenuate fibrosis and the macrophage response to chronic myocyte injury. We will use the swine HFpEF model to translate three promising antifibrotic interventions that are supported by mechanistic studies in rodent models of cardiac fibrosis but not translated to a large animal model of disease. Aim 1 will test the hypothesis that the development of the HFpEF phenotype can be prevented by limiting the recruitment of proinflammatory macrophages following repetitive pressure overload-induced myocyte injury with micelles loaded with a CCR2 inhibitor. Aim 2 will test the hypothesis that N-Acetyl-Seryl-Aspartyl-Proline (Ac-SDKP), a peptide inhibitor of fibrosis, can reverse established interstitial fibrosis and improve left ventricular compliance by attenuating the macrophage response to myocyte injury. Aim 3 will test the hypothesis that intracoronary cardiosphere derived cells can promote macrophage polarization to a reparative phenotype and improve LV compliance by reversing fibrosis as well promoting myocyte proliferation. Our long-term objective is to improve the care of Veterans with heart failure by developing a better understanding of the mechanisms leading to HFpEF and identifying novel targeted treatments that can prevent or reverse interstitial fibrosis to increase LV compliance.